Presentation Abstract

Session: AOS.709.01N-Sol Sherry Distinguished Lecture in Thrombosis and Treatment of Thrombotic Disease
Presentation: 17765 - A Specific Antidote for Dabigatran: Immediate, Complete and Sustained Reversal of Dabigatran Induced Anticoagulation in Healthy Male Volunteers
Pres Time: Monday, Nov 18, 2013, 9:30 AM - 9:45 AM
Location: Room C140
Pres. Time: Monday, Nov 18, 2013, 9:30 AM - 9:45 AM
Specialty: +709. Hemostasis, Thrombosis and Fibrinolysis
Keywords: Anticoagulation; Dabigatran; Hemostasis; Thrombin inhibitors
Authors: Stephan Glund, Joachim Stangier, Michael Schmohl, Boehringer Ingelheim GmbH & Co. KG, Biberach an der Riss, Germany; Marina De Smet, SCS Boehringer Ingelheim Comm. V., Brussels, Belgium; Dietmar Gansser, Benjamin Lang, Boehringer Ingelheim GmbH & Co. KG, Biberach an der Riss, Germany; Viktoria Moschetti, Boehringer Ingelheim GmbH & Co. KG, Ingelheim, Germany; Steven Ramael, SGS Life Science Services, Antwerpen, Belgium; Paul A Reilly, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT
Abstract: Introduction
The new oral anticoagulants are effective alternatives for warfarin but specific antidotes are not yet available for these agents to manage life-threatening bleeding or when emergency surgery is necessary. A specific antibody fragment (Fab) is being developed which binds dabigatran with high affinity and thereby prevents dabigatran inhibition of thrombin. For the first time in human volunteers, we determined whether equimolar doses of Fab would reverse the anticoagulant effects of dabigatran.
Methods
Safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of the Fab were investigated in a randomized, double-blind, placebo controlled study in 145 healthy male volunteers. In part I of the study, subjects received single rising i.v. doses of up to 8 g Fab. In part II, Fab doses of 1 g, 2 g and 4 g were administered as 5 min i.v. infusion in the presence of dabigatran (220 mg bid for 4 days). Concentrations of unbound dabigatran were determined as a measure of pharmacologically active dabigatran. The anticoagulant effect of dabigatran and its reversal were assessed by diluted Thrombin Time (Hemoclot® DTI assay), Thrombin Time (TT), activated Partial Thromboplastin Time (aPTT), Ecarin Clotting Time (ECT) and Activated Clotting Time (ACT).
Results
All administered doses of Fab were safe and well tolerated. PK measurements of unbound dabigatran indicated Fab binding and thus reversal of the anticoagulant effects of dabigatran directly after infusion. Prolongation of clotting times induced by dabigatran was reversed to baseline at the end of the 5 minute infusion of the antidote, as consistently demonstrated by all clotting assays. There was a dose-dependent reversal with increasing doses of antidote. Complete reversal lasted for ~30 min after administration of 1 g Fab. Reversal was complete and sustained in 7 of 9 subjects administered 2 g and in all subjects administered 4 g. In these subjects, TT, the most sensitive coagulation parameter, was reversed from a ratio of up to 14-fold over baseline to less than 2-fold.
Conclusions
The dabigatran antidote was well tolerated and led to immediate, complete and sustained reversal of dabigatran induced anticoagulation in healthy male volunteers.
Disclosures:   S. Glund, Employed by Boehringer Ingelheim GmbH and Co. KG, Significant,Employment; J. Stangier, Employed by Boehringer Ingelheim GmbH & Co. KG, Significant,Employment; M. Schmohl, Employed by Boehringer Ingelheim GmbH & Co. KG, Significant,Employment; M. De Smet, Employed by SCS Boehringer Ingelheim Comm. V., Significant,Employment; D. Gansser, Employed by Boehringer Ingelheim GmbH & Co. KG, Significant,Employment; B. Lang, Employed by Boehringer Ingelheim GmbH & Co. KG, Significant,Employment; V. Moschetti, Employed by Boehringer Ingelheim GmbH & Co. KG, Significant,Employment; S. Ramael, Principal Investigator, Significant,Other Research Support; P.A. Reilly, Employed by Boehringer Ingelheim Pharmaceuticals, Inc., Significant,Employment.
Dabigatran antidote used for reversal of the dabigatran anticoagulant effect



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